Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector
Reexamination Certificate
1997-01-31
2003-04-01
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
C424S193100, C424S278100, C424S093730, C514S025000, C536S004100, C530S395000, C530S813000
Reexamination Certificate
active
06540999
ABSTRACT:
BACKGROUND OF THE INVENTION
The T lymphocyte compartment of the immune system can be divided into a variety of cell subsets. For example, CD4
+
T cells represent the T helper cell subset, whereas CD8
+
T cells represent the cytotoxic T cell subset. Additionally, CD4
+
T helper cells mature into distinct subpopulations that produce different panels of cytokines: the T helper type 1 (Th1) subset produces interleukin-2 (IL-2), interferon-&ggr; (IFN-&ggr;) and tumor necrosis factor&bgr;, (TNF-&bgr;), whereas the T helper type 2 (Th2) subset produces interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL-6) and interleukin-10 (IL-10). The Th1 and Th2 subsets also have differing functional activities. Th1 cells are involved in inducing delayed type hypersensitivity responses, whereas Th2 cells are involved in providing efficient “help” to B lymphocytes and stimulate production of IgG1 and IgE antibodies. For a review of Th1 and Th2 subsets, see Seder, R. A. and Paul, W. E. (1994)
Ann. Rev. Immunol.
12:635-673.
Cytokines are thought to play a dominant role in controlling the differentiation of T helper precursors (Thp) to either the Th1 or Th2 lineage. Th 1-associated cytokines, such as IFN-&ggr;, can enhance the development of Th1 cells and inhibit the development of Th2 cells, whereas Th2-associated cytokines, such as IL-4 and IL-10, can enhance the development of Th2 cells and inhibit the development of Th1 cells. Thus, cytokines can reciprocally regulate the development and/or progression of either a Th1 or a Th2 response.
The course of certain disease states is influenced by whether a predominant Th1 response or Th2 response is mounted. For example, in experimental leishmania infections in mice, animals that are resistant to infection mount predominantly a Th1 response, whereas animals that are susceptible to progressive infection mount predominantly a Th2 response (Heinzel, F. P., et al. (1989)
J. Exp. Med.
169:59-72; Locksley, R. M. and Scott, P. (1992)
Immunoparasitology Today
1:A58-A61). In murine schistosomiasis, a Th1 to Th2 switch is observed coincident with the release of eggs into the tissues by female parasites and is associated with a worsening of the disease condition (Pearce, E. J., et al. (1991)
J. Exp. Med
173:159-166; Grzych, J-M., et al. (1991)
J. Immunol.
141:1322-1327; Kullberg, M. C., et al. (1992)
J. Immunol.
148:3264-3270). Many human diseases, including chronic infections (such as with human immunodeficiency virus (HIV) or tuberculosis) and certain metastatic carcinomas, also are characterized by a Th1 to Th2 switch, with elevated expression of IL-10 (see e.g., Shearer, G. M. and Clerici, M. (1992)
Prog. Chem. Immunol.
54:21-43; Clerici, M and Shearer, G. M. (1993)
Immunology Today
14:107-111; Yamamura, M., et al. (1993)
J. Clin. Invest.
91:1005-1010; Pisa, P., et al. (1992)
Proc. Natl. Acad. Sci. USA
89:7708-7712; Fauci, A. S. (1988)
Science
239:617-623). Furthermore, certain autoimmune diseases have been shown to be associated with a predominant Th1 response. For example, patients with rheumatoid arthritis have predominantly Th1 cells in synovial tissue (Simon, A. K., et al. (1994)
Proc. Natl. Acad. Sci. USA
91:8562-8566) and experimental autoimmune encephalomyelitis (EAE) can be induced by autoreactive Th1 cells (Kuchroo, V. K., et al. (1993)
J. Immunol
151:4371-4381).
Velupillai and Ham (
Proc. Natl. Acad. Sci. USA
(1994) 91:18-22) have shown that schistosome egg antigen (SEA), which expresses the Lewis
x
antigen, and conjugates of the Lewis
x
antigen, can stimulate IL-10 production in vitro by B cells from
Schistosoma mansoni
infected mice, but not B cells from uninfected mice, suggesting that during the course of
S. mansoni
infection, the observed Th1 to Th2 shift may results from IL-10 production by B cells induced by SEA. The significance of these observations beyond the particular
S. mansoni
system used, however, is unclear. For example, this work did not demonstrate whether human immune cells (e.g., human immune cells in the absence of
S. mansoni
infection) were responsive to Lewis antigen-containing compounds, nor whether cell types other than B cells, such as macrophages or T cells, could produce IL-10 in response to stimulation with compounds comprising a Lewis antigen in the absence of
S. mansoni
infection. Moreover, this work did not demonstrate whether Lewis antigen-containing compounds could stimulate production of other cytokines that regulate development of Th1 and Th2 responses, such as IL-4 or IL-5. Still further, this work did not demonstrate whether Lewis antigen-containing compounds were capable of modulating immune responses in vivo.
SUMMARY OF THE INVENTION
Given the role of either Th1 or Th2 cells in the development or progression of many disease states, methods for influencing whether a Th1 or Th2 response is mounted are desirable for a variety of clinical situations. This invention provide methods for modulating immune responses by modulating the interaction of immune cells with a compound comprising a Lewis antigen such that production by the immune cells of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. In particularly preferred embodiments, the methods of the invention can be used to stimulate an antigen-specific immune response in a subject (i.e., the compounds of the invention can be used as adjuvants) or to inhibit allergic responses in a subject. The methods of the invention further can be applied to other clinical situations, including autoimmune disorders, cancer and infectious diseases.
The invention is based, at least in part, on the discovery that stimulation of a variety of cell types, including human immune cells, T cells, macrophages and non-T, non-B splenic cells with Lewis antigen-containing conjugates results in the production of cytokines that regulate the development of Th1 or a Th2 response. Moreover, it has now been discovered that human immune cells are sensitive to stimulation by Lewis
y
antigen-containing conjugates, that cells from human allergy patients and cancer patients show responsiveness to Lewis antigens and that even normal human peripheral blood mononuclear cells are responsive to stimulation with Lewis-antigen containing compounds. It further has been discovered that Lewis antigen-containing conjugates can be used to stimulate production of a variety of Th2-associated cytokines, including IL-10, IL-4 and IL-5. It still further has been discovered that administration of Lewis-antigen containing compounds is effective for modulating immune responses in vivo. For example, stimulatory forms of the Lewis-antigen containing compounds of the invention can be administered to a subject to promote an antigen-specific immune response (e.g., antigen-specific IgG responses) in the subject. Alternatively, inhibitory forms of the Lewis-antigen containing compounds of the invention can be administered to a subject to inhibit IgE responses in the subject (e.g., in the treatment of allergies).
In one embodiment, the invention provides an immunomodulatory method comprising contacting a human immune cell with an agent that modulates interaction of a compound comprising a Lewis antigen with the human immune cell such that production by the human immune cell of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. The human immune cell can be, for example, a T cell, a macrophage or a B cell. In another embodiment, the invention provides an immunomodulatory method comprising contacting a macrophage with an agent that modulates interaction of a compound comprising a Lewis antigen with the macrophage such that production by the macrophage of at least one cytokine that regulates development of a Th1 or Th2 response is modulated. In yet another embodiment, the invention provides an immunomodulatory method comprising contacting a T cell with an agent that modulates interaction of a compound comprising a Lewis antigen with the T cell such that production by the T cell of at least on
Harn Donald A.
Velupillai Palanivel
DeConti, Jr. Giulio A.
Gambel Phillip
Kanik Cynthia L.
Lahive & Cockfield LLP
President and Fellows of Harvard College
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